Development of a Covalent Inhibitor of c‑Jun N‑Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1

The
c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated
protein kinase (MAPK) family, which includes JNK1–JNK3. Interestingly,
JNK1 and JNK2 show opposing functions, with JNK2 activity favoring
cell survival and JNK1 stimulating apoptosis. Isoform-selective small
molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological
probes but have been difficult to develop due to the similarity of
their ATP binding pockets. Here, we describe the discovery of a covalent
inhibitor YL5084, the first such inhibitor that displays selectivity
for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond
with Cys116 of JNK2, exhibits a 20-fold higher Kinact/KI compared to that of JNK1,
and engages JNK2 in cells. However, YL5084 exhibited JNK2-independent
antiproliferative effects in multiple myeloma cells, suggesting the
existence of additional targets relevant in this context. Thus, although
not fully optimized, YL5084 represents a useful chemical starting
point for the future development of JNK2-selective chemical probes.